The U-2 crashed in the UAE on Wednesday while approaching the base to land, a Pentagon official said, speaking on the condition of anonymity because of the sensitivity of the operation.
Early reports gave no indication of any hostile fire, but it is too soon to be certain why it crashed, the official said.
The 380th Air Expeditionary Wing has been based at the al-Dhafra air base near Abu Dhabi, in the UAE, since early 2002 in support of Operation Enduring Freedom.
It flies various types of aircraft, including aerial refuelling tankers and the Global Hawk - a pilotless plane about the size of a Boeing 737.
General Richard Myers, chairman of the Joint Chiefs of Staff, visited the wing in August.
The U-2 is a reconnaissance plane that operates at an altitude of more than 70,000 feet and has been used in every major conflict the US has fought since the aircraft was developed in the 1950s.
Flying beyond the range of most surface-to-air missiles, it was famously shot down in 1960 over the Soviet Union.
With its bicycle-type gear and the challenges of handling the aircraft at low altitudes, the U-2 requires a high degree of precision during landing.
The location of the U-2 crash was
not disclosed by the US military
Forward visibility is limited, partly because of the extended nose.
A second pilot normally "chases" the U-2 while it lands, assisting the pilot by providing information on altitude and runway alignment.
The US military did not immediately release the location or circumstances of the crash because it did not want to create problems for the nation where the plane went down.
Officials also withheld the name of the pilot pending notification of relatives.
US Central Command said only that the crash occurred in "Southwest Asia", a term that can be a substitute for the Middle East.
"The specific location is not releasable due to host nation sensitivities," US Air Force Captain David W Small, a Central Command spokesman, said in an e-mail.
"The site of the crash has been secured to ensure the safety of local citizens and the integrity of the site for investigation team members," a military announcement said.
"The site of the crash
has been secured to ensure the safety of local citizens and the integrity of the site for investigation team members"
US military statement
In Washington, Lieutenant-Colonel Barry Venable, a Pentagon spokesman, said the plane had completed a mission related to Operation Enduring Freedom, the code name for American operations in Afghanistan.
There has been heavy fighting in southern Afghanistan in recent days, with American fighter planes bombarding rebel hideouts with missiles and bombs, killing up to 76 fighters in combat on Tuesday and Wednesday.
A US security team was at the site of the crash, Venable said.
The 380th Air Expeditionary Wing's commander, Colonel Darryl Burke, appointed an interim investigation board to determine the cause of the crash.
It was not clear when the results of the investigation would be completed.
The U-2 has been used by the US for decades, and the new model, the U-2S, entered service in 1994 - 39 years after the first plane went into operation.
The U-2 has seen extensive use
in Afghanistan and Iraq
There are just 36 in the world, 29 being used by the Air Force, five two-seat trainers and two used for high-flying Nasa research.
The plane saw extensive use in both Afghanistan and Iraq, before, during and after the war.
In February 2003, then-secretary of state Colin Powell said Iraq was violating a UN resolution by rejecting U-2 reconnaissance flights.
The planes also were used in the 1991 Gulf War, and employed with great success by UN weapons inspectors in Iraq in the 1990s to uncover advanced weapons development centres, which were later destroyed.
In January 2003, a U-2 crashed in South Korea. The pilot ejected to safety, but four Koreans on the ground were injured.
A U-2 was shot down 1 May 1960 over Soviet territory while photographing Soviet missile installations. After parachuting to safety, pilot Francis Gary Powers was captured and later convicted as a spy.
He was held for almost two years before being traded for a KGB captive.